The benefits of statins are undisputed in reducing the risk of coronary heart disease and the progression of coronary atherosclerosis. Nevertheless, associated complications can be life-threatening. More than 19 million people in the U.S. take statins. Up to 7% (>1.3 million) will develop muscle symptoms and 0.1 to 0.2% (>19,000) may develop life-threatening myopathies. Our long-term goal is to identify clinically significant genetic variants associated with statin myopathy, a complex disorder with diverse etiologies. Our hypothesis is that the genetic architecture of susceptibility to statin myopathy is complex and will include an increased prevalence of underlying hereditary muscle disorders as well as genetic variation in genes with broad regulatory roles in cellular metabolism and structure. This hypothesis is based on preliminary findings of significantly increased mutant alleles causative for 3 common metabolic myopathies in patients with statin myopathy vs. statin-tolerant patients (p=0.04). Up to 16- and 10-fold increases in mutant allele frequencies exist for McArdle disease and carnitine palmitoyltransferase II deficiency, respectively. Defects in energy metabolism were found in muscle in 50% of patients. Aim 1 will expand the number of candidate disorders and mutations evaluated in patients with statin myopathies (560 severe cases;295 mild cases) in a case-control comparison with statin-tolerant individuals (n = 400), patients with non-statin myopathies (n = 640), and individuals in the general population not exposed to statins (n = 300). Individuals who are carriers for or affected with known metabolic myopathies and take statins (n = 100) will be included to test the hypothesis that they will be at increased risk for muscle symptoms while on statin therapy. Aim 2 will identify and characterize clinically significant associations between single nucleotide polymorphisms and statin myopathies in a case- control genome-wide association study of pooled DNA samples using microarray analysis. Preliminary studies have identified a highly associated notch-like gene (p<0.001 vs. combined control groups) localized in muscle and CNS tissue and predicted to have a role in regulatory properties of muscle regeneration. Expression studies are proposed for the predicted protein. Additional genetic variants will be identified using the same strategy. Statistical analyses for power, effect size and patterns of linkage disequilibrium will be central to the validation of our findings. Two-thirds of patients referred with severe statin myopathies have persistent and, in some cases, progressively incapacitating symptoms of long duration post-therapy. Many of these outcomes will be preventable with appropriate identification of genetic risk factors, monitoring of drug dosage, and regular blood testing for indicators of muscle damage. With the increasing use of these important drugs, not only for cholesterol-lowering goals but for other health-related applications, the identification of underlying hereditary risk factors will lead to cost-effective screening, reduced morbidity, lower health care costs relevant to adverse outcomes, and increased understanding of the pharmacogenomics of statin myopathies. PUBLIC HEALTH RELEVANCE. Many patients with severe muscle symptoms from statin therapy to lower blood cholesterol have persistent and, in some cases, progressively incapacitating symptoms of long duration post-therapy. Many of these outcomes will be preventable with appropriate identification of genetic risk factors, monitoring of drug dosage, and regular blood testing for indicators of muscle damage. With the increasing use of these important drugs, not only for cholesterol-lowering goals but for other health-related applications, the identification of underlying hereditary risk factors will lead to cost-effective screening, reduced morbidity, and lower health care costs relevant to adverse outcomes.